MXPA99005660A - New aqueous medicament preparations for the production of propellent gas-free aerosols - Google Patents

Abstract

The invention relates to medicament preparations in the form of aqueous solutions for the production of propellent gas-free aerosols.

Description

New aqueous drug preparations for the production of propellent gas-free aerosols DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical preparations in the form of aqueous solutions for the production of propellant gas-free aerosols for inhalation. The application of dosing aerosols has been the fixed component in the therapy of obstructive pulmonary diseases, especially asthma, in the last 20 years. Typically fluorocarbon hydrocarbons were used as propellant gases. After the harmful potential of these propellant gases for ozone had been recognized, numerous efforts were made to develop alternatives to them. As an alternative, the development of vaporizers is offered, in which, at high pressure, aqueous solutions of pharmacologically active principles are sprayed, in such a way that mists of inhalable particles are formed. The advantage of these vaporizers is that the use of propellant gases can be completely dispensed with. REF .: 30528 Such vaporizers are described, for example, in the patent application PCT 091/14468, to whose content reference is made therewith. In the vaporizers described there, solutions of defined volumes, containing active principles, are sprayed through small nozzles, using high pressures, so that inhalable aerosols with an average particle size between 3 and 10 micrometers are formed. A more developed embodiment of the vaporizers mentioned above is described in PCT / EP96 / 04351. The vaporizer ® shown in Figure 6 bears the Respimat mark. Usually, the medicinal principles intended for inhalation are dissolved in a solution, aqueous or ethanolic, mixtures of solvents based on water and ethanol being also suitable, according to the solvent properties of the active principles. Other components of the solvent are, together with water and / or ethanol, optionally other cosolvents and, likewise, the drug preparation may contain flavoring substances and other pharmacological adjuvants. Examples of cosolvents are those containing hydroxyl groups or other polar groups, for example alcohols - especially iso-propyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and fatty acid-polyoxyethylene esters. The cosolvents are suitable for increasing the solubility of the adjuvants and, if necessary, of the active ingredients. The portion of drug principle dissolved in the finished drug preparation is between 0.001 and 30% - preferably between 0.05 and 3%, especially 0.01 to 2% (weight / volume). The maximum concentration of the drug principle depends on the solubility in the solvent and the dosage required to achieve the desired therapeutic activity. In the new preparations, all substances suitable for administration by inhalation and which are soluble in the abovementioned solvents can be used as medicament principles. Of special interest are the medicinal principles for the treatment of diseases of the respiratory tract. Therefore, they are especially betamimetics, anticholinergics, antiallergics, antihistamines and steroids, as well as combinations of active ingredients based on those.

In serial tests it was now found that the vaporizers described at the beginning may present spray anomalies, in the case of using aqueous solutions of medicaments (bidestilated or demineralized water (ion exchanger) is usually used as the solvent). These spray anomalies are presented as a modification of the aerosol spray table, with the consequence that, in the extreme case, due to the modified average particle size distribution (modification of the aerosol portion accessible to the lung), an exact dosage of the individual dose to be applied to the patient can no longer be guaranteed. These spray anomalies occur, in particular, when the vaporizer is operated at intervals, for example with rest periods of approximately 3 or more days between individual operations. Possibly, these anomalies, which in the extreme case can lead to the failure of the device, are attributable to microscopic depositions in the area of the outlet of the nozzle. Surprisingly, it was discovered that these spray anomalies no longer appear, when the aqueous medicinal preparations to be sprayed contain an effective, defined amount of a complexing agent, especially of EDTA (ethylenediaminetetraacetic acid) or, respectively, of their salts . The aqueous pharmaceutical preparations according to the invention contain water as the solvent, and optionally, to increase the solubility, ethanol can be added up to 70% (v / v >); , preferably between 30 and 60% (v / v). Other pharmacological adjuvants may be added, such as for example preservatives, especially benzalkonium chloride. The preferred amount of preservative, especially benzalkonium chloride, is between 8 and 12 mg / 100 ml of solution. Suitable complexing agents are those that are pharmacologically tolerable, especially those that are already legally permitted as medicaments. Particularly suitable are EDTA, nitrilotriacetic acid, citric acid and ascorbic acid, as well as their salts. Especially preferred is the disodium salt of ethylenediaminetetraacetic acid. The number of complexing agents is chosen so that an effective amount of complexing agents is added, so that spray anomalies no longer appear.

For the complex former EÉ > However, the effective amount is between 10 and 1000 mg / 100 rolls of solution, especially between 10 and 100 mg / 100 ml of solution, the preferred range of the amount of complex phonand is between 25 and 75 mg / 100 ml of solution, in particular between 25 and 50 mg / 100 ml of solution »In principle, the following compounds can be used as active ingredient or combination of active ingredients in the aqueous medicinal preparation according to the invention. In isolated cases, to improve the solubility it may be necessary to use a higher ethanol content or, also, a dissolution inducer. Tyrotropium bromide ^ 3- (hydroxydi-2-thienylacetyl) oxy] -8, 8-dimethyl, azoniafc-cyclocline bromide, 2,1] oct-6-ene As beta-mimetics: bambuteroi bitolterol carbuterol formoterol clenbutersi fenoterol hexsprenaline prscatersl ibuterol pirbuterol salmeterol tulobtrterol reproterol saI umal siit ftexbji ftexbji na 1- (2-fluoro-4-f? Idroxyphenyi) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, erythro-5 '-hydrox -8' - (1-hydroxy) 2-isopropylaminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butyl-amino) ethanol, 1- ( 4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol. As anticholinergics: ipratropium bromide oxitropium bromide trospium chloride benzyl-N-β-fluoroetiinopropetic acid ester ester bromide As steroids: budesonide - * beclomethasone (and, respectively, 17,21-dipropionate) 21-isonicotinate dexamethasone flunisolide As antiallergics: disodium cromoglycate nedocromil epinastine Examples of steroids that can be used as an active ingredient in the pharmaceutical preparation according to the invention are: Seratrodate Mycophenolate mofetil Pranlucan Zileutone Butixocort Budenoside Deflazacort Fluticasone Promedrol Mometasone furoate Tipredano Beclometasone, Douglas Icometasona embutato Ciciómetasona Cloprednol Fluocortin butyl Halometasone Deflazacort Alelómethasone Cyclomethasone Alisactide Prednicarbate Hydrocortisone butyrate-propionate Tixocortol pivalate Aclometasone dipropionate Lotrisone Canesten-HC Deprodona fluticasone propionate Methyl Acetase Halopredone Acetate Prednisolone Mometasone Mometasone Furoate Hydrocortisone Acetate Mometasone Ilebetasol Propionate Aminoglutethimide Triamcinolone Hydrocortisone Meprednisone Fluorornetolone Dexamethasone Betamethasone Medrisone Acetate of fluclorolone Fluocinolone acetonide Acetate for etasone Deprodone propionate Aristocort diacetate Fluocinonide Mazipredone Difluprednate betamethasone valerate Issnicotinate of Dexamethasone dipropionate beclomethasone Capcobate of flucortolone Formocortal Hexacetonide of Cloprednol Triamcinolone Formebolone Clobetasone Endrisone Flunisolide Halcinonide Fluazacort Clobetasol 17-butyrate of hydrocortisone Diflorasona Fluocortin Amcinonide Dipropionate of betamethasone Cortivazole Adamanthoate of betamethasone Fluodexan Trilostane Budesonide Clobetasone Demetex Benetonide trimacinolone 17-propionate of the 9-alpha acid methyl ester. -cloro-6 lfa -fluoro-11.beta .17. alpha -dihydroxy-16.alpha.-methyl ^ 3 = oxo ^ l, 4-androstadiene = 17. beta.-carboxylic acid. Other active ingredients particularly suitable for the production of aqueous medicinal preparations for administration by inhalation are: β-sympathomimetic; for example fenoterol, salbutamol, formoterol, terbutaline; anticholinergic; for example ipatropium, oxitropium, tiotropium; steroids; for example beclomethasone dipropionate, budesonide, flunisolide; peptides; for example insulin; analgesics; for example fentanyl. It is understood by itself that, if necessary, pharmacologically tolerable salt forms are used, which dissolve in the solvents according to the invention. In what follows, through examples, the advantage of the drug preparation according to the invention is explained in more detail. As solution of medicinal principle, solution of ipratropium bromide (c = 333 mg / 100 ml) with the pH value of 3.4 and the preservative benzalkonium chloride (c = 10 mg / 100 ml) was used. The solutions tested either did not contain EDTA or contained EDTA at the concentration c = 0.1 mg, 1 mg, 50 mg and 75 mg / 100 ml as the disodium salt. For the test, new Respi t devices were used in each case (technical data: volume of the drug preparation administered, approximately 15 μl, pressure, approximately 300 bar, 2 jets impelled from two nozzle openings of size 5 x 8 μm) . The way to carry out the impulse was set for the test in such a way that the devices worked 5 times, then they rested for 3 days, and then they worked again 5 times, and they continued working with this rhythm of intervals. In each series of measurements, 15 apparatuses were tested, the results and, respectively, spray anomalies, are compiled in Table 1.

Table 1 • Formulation examples (for fenoterol and ipratropium bromide) Analogously to the previous examples, the following solutions were prepared.

* In the form of disodium salt. For the active substances, depending on the dose per pulse and their solubility, a range of concentrations of 10 mg to 20,000 mg / 100 ml can be considered. The indicated dosages are calculated on the basis of a therapeutically effective individual dosage of approximately 12 microliters per pulse. In the case of a modified volume of the individual dosage, the concentrations of the active principle of the drug preparations can be modified. For the complexing agent (for example EDTA = diNa), the concentration range is between 10 and 1000 mg / 100 ml (also depending on the pH value of the solution). The preferred range is between 25 mg and 100 mg / 100 ml. The amount of benzalkonium chloride should be in the range of 8 to 12 mg / 100 ml.

The solutions were adjusted to a pH of 3.2 and, respectively, 3.4, with 0.1 N HCl and, respectively, 1 N. All the concentration data refer to 100 ml of finished solution of active principle.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (8)

CLAIMS Having described the invention as above, the content of the following claims is claimed as a property:

1. Use of aqueous drug preparations to produce propellant gas free aerosols for inhalation, characterized in that the drug preparation contains a complex former.

2. Use according to claim 1, characterized in that the active substance is selected from the group of betamimetics, anticholinergics, antiallergics and / or antihistamines.

3. Use according to claim 1 or 2, characterized in that the active substance is selected from the group of phenotrol, ipatropium bromide, berotec, atrovent, berodual, salbutamol, combivent, salbutamol, Ba 679 Br, BEA 2108 Br. Oxivent.

4. Use according to claims 1 to 3, characterized in that the complexing is nitrilotriacetic acid, citric acid, ascorbic acid or its salts.

5. Use according to claim 1 to 4, characterized in that the complex formed is EDTA or its salts.

6. Use according to claim 5, characterized in that the concentration of the complex former is between 25 and 75 mg.

7. Use according to one of claims 1 to 6, characterized in that the drug preparation contains up to 70% ethanol.

8. Use according to one of claims 1 to 7, characterized in that it contains the active substance in a concentration of 0.001 to 2 g / 100 ml. from solution.